EP1795535A1 - Procécdé de fabrication d'une solution stable du 1,3,4,6-tetra-O-acetyl-2-O-trifluorométhane-sulfonyl-beta-D-mannopyranose (triflate de mannose) - Google Patents
Procécdé de fabrication d'une solution stable du 1,3,4,6-tetra-O-acetyl-2-O-trifluorométhane-sulfonyl-beta-D-mannopyranose (triflate de mannose) Download PDFInfo
- Publication number
- EP1795535A1 EP1795535A1 EP05026889A EP05026889A EP1795535A1 EP 1795535 A1 EP1795535 A1 EP 1795535A1 EP 05026889 A EP05026889 A EP 05026889A EP 05026889 A EP05026889 A EP 05026889A EP 1795535 A1 EP1795535 A1 EP 1795535A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- solution
- container
- solvent
- acetonitrile
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- OIBDVHSTOUGZTJ-PEBLQZBPSA-N [(2r,3r,4s,5s,6s)-3,4,6-triacetyloxy-5-(trifluoromethylsulfonyloxy)oxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O OIBDVHSTOUGZTJ-PEBLQZBPSA-N 0.000 title abstract description 29
- 238000000034 method Methods 0.000 title abstract description 21
- 238000004519 manufacturing process Methods 0.000 title description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 60
- 239000002904 solvent Substances 0.000 abstract description 21
- 150000007960 acetonitrile Chemical class 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 13
- 239000000463 material Substances 0.000 abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 238000011049 filling Methods 0.000 abstract description 3
- 239000011148 porous material Substances 0.000 abstract description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 52
- 150000001875 compounds Chemical class 0.000 description 15
- 239000012535 impurity Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000002243 precursor Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000012080 ambient air Substances 0.000 description 8
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- 239000011521 glass Substances 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001471 micro-filtration Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 229920005549 butyl rubber Polymers 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000002600 positron emission tomography Methods 0.000 description 3
- AOYNUTHNTBLRMT-MXWOLSILSA-N 2-Deoxy-2(F-18)fluoro-2-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H]([18F])C=O AOYNUTHNTBLRMT-MXWOLSILSA-N 0.000 description 2
- WEVYAHXRMPXWCK-MICDWDOJSA-N 2-deuterioacetonitrile Chemical compound [2H]CC#N WEVYAHXRMPXWCK-MICDWDOJSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229920005556 chlorobutyl Polymers 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000012217 radiopharmaceutical Substances 0.000 description 2
- 229940121896 radiopharmaceutical Drugs 0.000 description 2
- 230000002799 radiopharmaceutical effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000208199 Buxus sempervirens Species 0.000 description 1
- JZNGJEBWTQYCFY-JMMWHDCWSA-N CC(C([C@H](O)OCCO)F)O Chemical compound CC(C([C@H](O)OCCO)F)O JZNGJEBWTQYCFY-JMMWHDCWSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- SHBHJRVMGYVXKK-XVIXHAIJSA-N [(2r,3r,4r,5s,6s)-3,4,6-triacetyloxy-5-hydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@@H](O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O SHBHJRVMGYVXKK-XVIXHAIJSA-N 0.000 description 1
- IEOLRPPTIGNUNP-PEBLQZBPSA-N [(2r,3r,4s,5s,6r)-3,4,5-triacetyloxy-6-hydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O IEOLRPPTIGNUNP-PEBLQZBPSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000002788 crimping Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000012454 limulus amebocyte lysate test Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 238000000711 polarimetry Methods 0.000 description 1
- -1 polytetrafluoroethylene Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
Definitions
- the invention relates to a process for the preparation of stable solutions of 1,3,4,6-tetra- O- acetyl-2- O trifluoromethanesulfonyl- ⁇ -D-mannopyranose (Mannosetriflat). It further relates to a mannose triflate solution obtained by this process.
- 1,3,4,6-Tetra- O- acetyl-2- O- trifluoromethanesulfonyl- ⁇ -D-mannopyranose is a starting material for the preparation of 2- [ 18 F] fluoro-2-deoxy-D glucose (FDG), which is used as a radiopharmaceutical in positron emission tomography (PET).
- FDG fluoro-2-deoxy-D glucose
- Positron emission tomography is a method by which pathological processes in the human organism can be visualized at the molecular level.
- the patient is injected with a compound labeled with a radioactive isotope and the distribution of the activity is measured by means of a PET camera.
- isotopes include F-18 and C-11.
- 2- [ 18 F] fluoro-2-deoxy-D-glucose (FDG) is currently the most widely used radiopharmaceutical.
- FDG FDG takes place according to the method of Hamacher ( K. Hamacher, HH Coenen, G. Stoecklin, J. Nucl. Med. 1986, 27, 235-238 ).
- Mannosetriflate is reacted as a precursor in the presence of Kryptofix [2.2.2] with 18 F-fluoride and saponified the obtained intermediate 2- [ 18 F] -fluoro-2-deoxyglucosetetraacetat either acidic or basic.
- This method is currently used in so-called synthesis modules for the supply of FDG.
- the synthesis module Tracerlab MX from General Electric (GE) works with 20 to 60 mg mannosetriflate as precursor, which is dissolved in a solvent immediately before the start of the synthesis.
- the specific activity of the obtained FDG is between 2 and 5 Ci / ⁇ mol.
- the specific activity of 2 Ci / ⁇ mol 18 F-fluoride corresponds approximately to a molar amount of 1 nmol.
- Microfluidics and microreactor technology offer an approach to this. Optimum reaction conditions (laminar flow, excellent thermal mixing, rapid reactions) lead to a dramatic increase in yields, in particular the radio yield and a reduction in the number of by-products.
- portioning and dosing of precursors should be done on a microgram scale. That's it Although still by a factor of 1000 above the actual required quantities of substance, but approaches the ideal conditions already strong.
- mannose triflate is acetonitrile or deuterated acetonitrile.
- solutions of mannosetriflate are only stable for a short time at room temperature. Therefore, solutions of mannosetriflate in acetonitrile or deuterated acetonitrile will not be produced until immediately (maximum one to two hours prior to conversion to FDG.
- the object of the invention is to eliminate the disadvantages of the prior art. It is intended in particular to specify a process with which storage-stable solutions of mannose triflate in acetonitrile and deuterated acetonitrile can be prepared. Furthermore, a storage-stable solutions of mannosetriflate in acetonitrile and deuterated acetonitrile should be given, which can be obtained by this method.
- the compound of formula 1 is 1,3,4,6-tetra- O- acetyl-2- O- trifluoromethanesulfonyl- ⁇ -D-mannopyranose, also referred to as mannosetriflate or TATM.
- Acetonitrile is a compound of formula (II); deuterated acetonitrile, a compound of formula (III), which is also referred to as deuteroacetonitrile.
- CH 3 -C ⁇ N (I) CD 3 -C ⁇ N (II)
- step (a) refers to the total weight of the provided compound of formula (I) and all impurities contained in it.
- step (b) % by weight refers to the total weight of the solvent provided and any impurities contained therein.
- the inventive method allows the storage of the solution at room temperature, so that the previously required, consuming storage of undissolved Mannosetriflats omitted in freezers and thus the transport of solutions of Mannosetriflats in acetonitrile is significantly simplified.
- the method allows for providing the solution in ampoules or vials containing a predetermined amount of the solution at a given concentration of mannosetriflate. In this way, a simplification of the routine production of FDG can be achieved, which is a prerequisite for its preparation in microreactors, but also leads to an improvement in the production in conventional synthesis modules.
- the compound of formula I provided in step (a) contains at most 0.2% by weight of impurities belonging to the group consisting of 2,3,4,6-tetra-O-acetyl- ⁇ -D- mannopyranose (1-OH-tetraacetyl-mannose, 1-OH-TAM), 1,3,4,6-tetra- O- acetyl- ⁇ -D-mannopyranose (2-OH-tetraacetyl-mannose, 2-OH-TAM) and mixtures thereof consists.
- 1-OH-TAM, 2-OH-TAM are structurally similar compounds to mannosetriflate which, it has been found, can initiate decomposition of mannose triflate in acetonitrile.
- the compound of the formula I provided in step (a) should preferably contain at most 0.25% by weight of cyclohexane, at most 0.18% by weight of dichloromethane, at most 0.01% by weight of pyridine and at most 0.10% by weight. - contain% ethanol.
- the acetonitrile should have a purity of at least 99.9% and a water content of at most 0.05% by weight.
- the deuterated acetonitrile should have an isotopic enrichment of 99.8% and a water content of at most 0.05% by weight.
- Step (c) should be performed in ambient air containing no more than 350,000 particles of 0.5 ⁇ m or larger per cubic meter of ambient air and no more than 2,000 particles of 5 ⁇ m or larger per cubic meter of ambient air. This complies with the specifications of cleanroom class C according to the GMP directive.
- the Concentration of the solution is preferably adjusted to 0.1 to 1000 mg / ml.
- microfiltration according to step (d) should be conveniently carried out in an ambient air containing at most 3500 particles of 0.5 ⁇ m or larger per cubic meter of ambient air and no particles of 5 ⁇ m or larger per cubic meter of ambient air , This complies with the requirements of clean room class A according to the GMP directive.
- the solution is transferred under protective gas, for example argon or nitrogen, into the container according to step (e).
- protective gas for example argon or nitrogen
- the container in which the solution is filled according to step (e) is preferably sterilized by means of ⁇ radiation before the solution is filled into the container.
- the container is particularly preferably a glass container, for example an ampoule, vial or vial.
- the glass from which the glass container is made should belong to hydrolytic glass class 1 according to DIN EN ISO 8362-1.
- the closure of the container is preferably made of chlorobutyl rubber.
- the closure is preferably coated with an inert material such as polytetrafluoroethylene (PTFE), such as Flurotec®.
- PTFE polytetrafluoroethylene
- the precursor may also be mechanically secured to the container, for example by crimping.
- the container and closure must be chosen so that no moisture or air can enter the container after it has been closed. Furthermore, from the container and the closure no substances in the solution which could initiate decomposition of mannosetriflate.
- a solution of the compound according to formula (I) is also in a solvent selected from the group consisting of acetonitrile, deuterated acetonitrile and mixtures thereof provided by the process of the invention.
- mannose triflate manufactured by ABX GmbH, Radeberg, Germany
- Method specifies the method according to which the respective value of the specification is to be determined.
- Table 1 ⁇ / u> parameter specification method properties colorless to yellowish acicular crystals, odorless, soluble in acetonitrile organoleptic, visual identity - Spectrum comparison Comparison with Ph. Eur.
- the acetonitrile used as solvent had the following properties: purity: at least 99.9%, water content: at most 0.05 wt .-%.
- the deuterated acetonitrile used as solvent had the following properties: isotopic enrichment: 99.8%, water content: at most 0.05 wt .-%.
- the dissolution was carried out at room temperature, an atmospheric humidity of 60 ⁇ 20% and a particle concentration in the ambient air, which corresponded to the clean room class C according to the GMP directive.
- the microfiltration was carried out at room temperature, with an atmospheric humidity of 60 ⁇ 20% and a particle concentration in the ambient air that complied with the clean room class A according to the GMP directive.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05026889A EP1795535A1 (fr) | 2005-12-08 | 2005-12-08 | Procécdé de fabrication d'une solution stable du 1,3,4,6-tetra-O-acetyl-2-O-trifluorométhane-sulfonyl-beta-D-mannopyranose (triflate de mannose) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05026889A EP1795535A1 (fr) | 2005-12-08 | 2005-12-08 | Procécdé de fabrication d'une solution stable du 1,3,4,6-tetra-O-acetyl-2-O-trifluorométhane-sulfonyl-beta-D-mannopyranose (triflate de mannose) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1795535A1 true EP1795535A1 (fr) | 2007-06-13 |
Family
ID=36190787
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP05026889A Withdrawn EP1795535A1 (fr) | 2005-12-08 | 2005-12-08 | Procécdé de fabrication d'une solution stable du 1,3,4,6-tetra-O-acetyl-2-O-trifluorométhane-sulfonyl-beta-D-mannopyranose (triflate de mannose) |
Country Status (1)
| Country | Link |
|---|---|
| EP (1) | EP1795535A1 (fr) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005086612A2 (fr) * | 2003-07-29 | 2005-09-22 | Immunomedics, Inc. | Conjugues glucidiques fluores |
| US20050232387A1 (en) * | 2004-04-20 | 2005-10-20 | Padgett Henry C | Microfluidic apparatus and method for synthesis of molecular imaging probes |
-
2005
- 2005-12-08 EP EP05026889A patent/EP1795535A1/fr not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005086612A2 (fr) * | 2003-07-29 | 2005-09-22 | Immunomedics, Inc. | Conjugues glucidiques fluores |
| US20050232387A1 (en) * | 2004-04-20 | 2005-10-20 | Padgett Henry C | Microfluidic apparatus and method for synthesis of molecular imaging probes |
Non-Patent Citations (3)
| Title |
|---|
| CHAAR, M. R. ET AL: "Identification of 2-chloro-2-deoxyglucose (2-CIDG) and D-glucose as impurities formed in the synthesis of 2-[18F]fluoro-2-deoxyglucose (2-18FDG)", APPLIED RADIATION AND ISOTOPES , 45(2), 267-70 CODEN: ARISEF; ISSN: 0883-2889, 1994, XP002378913 * |
| CHIRAKAL, RAMAN ET AL: "Base-mediated decomposition of a mannose triflate during the synthesis of 2-deoxy-2-18F-fluoro-D-glucose", APPLIED RADIATION AND ISOTOPES , 46(3), 149-55 CODEN: ARISEF; ISSN: 0969-8043, 1995, XP000676184 * |
| KUGE, YUJI ET AL: "Chemical impurities in [18F]FDG preparations produced by solid-phase 18F-fluorination", NUCLEAR MEDICINE AND BIOLOGY , 29(2), 275-279 CODEN: NMBIEO; ISSN: 0969-8051, 2002, XP004334826 * |
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